TNF-α was discovered in 1975 as an endogenous protein having a necrotic activity against tumor cells (Carswell, E. A. et al., Proc. Natl. Acad. Sci. U.S.A. 1975, 72, 3666-3670). At present, TNF-α is recognized as one of the cytokines secreted from macrophages, monocytes and the like activated by exogenous and endogenous factors and to be widely involved in regulation of various cytokines production and protection from infectious diseases. However, persistent and excessive production and secretion of TNF-α cause overproduction of pro-inflammatory cytokines, apoptosis of cells, interference of intracellular signal transduction and the like, resulting in the primary and secondary tissue injury, and eventually becomes a factor responsible for etiology and exacerbation of various diseases (Aggarwall B. B., Puri R. K., eds. 1995. Human Cytokines: Their Role in Disease and Therapy. Cambridge, Mass., USA: Blackwell Sci.). Accordingly, for the treatment of disease conditions likely to be caused by an excessive production and secretion of TNF-α, it seems important to suppress the production and secretion of TNF-α or the action of TNF-α. Examples of these diseases in which TNF-α participates include many diseases, for example, commencing with rheumatoid arthritis, systemic lupus erythematosus (SLE), Crohn's disease, Behchet's disease, multiple sclerosis, arteriosclerosis, myasthenia gravis, diabetes mellitus, sepsis, acute infectious disease, asthma, atopic dermatitis, fever, anemia and the like.
As examples of the above treatment, it has already been reported that a human anti-TNF-α chimeric antibody and a TNF-α receptor (p75)-Fc fusion protein, both of which are biologics, are effective for rheumatoid arthritis patients (Elliott, M. et al., Lancet 1994, 344, 1105-1110; Moreland L. W. et al., N. Engl. J. Med. 1997, 337, 141-147). However, these biologics are pointed out to have problems such as; (a) generally expensive, (b) there is no option for their administration routes except for injection, thereby putting a considerable burden on patients, and (c) their administration may trigger the immune response and their effect may be lowered at the second and subsequent administration (Feldmann, M., et al., Adv. Immunol., 1997, 64, 283-350).
Therefore, in order to overcome the above various problems associated with biologics, a number of studies have been carried out on low molecular weight compounds which inhibit the production and secretion of TNF-α or suppress its action (Newton, R. C. et al., J. Med. Chem. 1999, 42, 2295-2314).
On the other hand, TACE (otherwise known as ADAM 17) is a membrane-bound proteinase, having a zinc at the catalytic site thereof, classified in the ADAM (a disintegrin and metalloproteinase) family (Black, R. A. et al., Nature 1997, 385, 729-733; Moss, M. L. et al., Nature 1997, 385, 733-736). It has been reported that TACE cleaves membrane-bound TNF-α (pro-TNF-α) to generate soluble TNF-α and that 90% of soluble TNF-α is produced by the enzymatic action of TACE based on an experiment performed with TACE knock out mouse (Black, R. A. et al., Nature 1997, 385, 729-733). On the other hand, it has been suggested from an in vitro experiment that ADAM-10 belonging to the same family as TACE also participates in the release of TNF-α, but the recent experimental results obtained using an antisense or an ADAM-10 inhibitor have suggested that ADAM-10 is not involved in the release of TNF-α (Condon, T. P., et al., Antisense & Nucleic Acid Drug Development 2001, 11, 107-116; Moss, M. L., et al., Drug Discovery Today 2001, 6, 417-426). In other words, this suggests that the only enzyme responsible for the release of TNF-α from pro-TNF-α is TACE. Thus, compounds which inhibit the enzymatic action of TACE are likely to suppress the production of soluble TNF-α, thereby serving as a therapeutic drug for the above various disease conditions caused by TNF-α. From the foregoing, studies on compounds which are likely to be associated with the action of inhibiting TACE have become active (Nelson, F. C. et al., Exp. Opin. Invest. Drugs 1999, 8, 383-392).
Matrix metalloproteinases (otherwise known as matrixin) (MMP) are proteinases having a zinc at the catalytic site thereof and degrade extracellular matrices. There are about 20 known MMPs which are suspected to participate in a variety of disease states. Although their in vivo actions have not been fully elucidated, studies on their inhibitors are being very actively developed (Whittaker, M. et al., Chem. Rev. 1999, 99, 2735-2776; Motoo Nakajima, TANPAKUSHITSU KAKUSAN KOUSO 2000, 45, 1083-1089; Connell, R. D. et al., Exp. Opin. Ther. Patents 2001, 11, 77-114).
Compounds which inhibit MMP had been reported to inhibit the production of TNF-α as well (Mohler, K. M. et al., Nature 1994, 370, 218-220; Gearing, A. J. H. et al., Nature, 1994, 370, 555-557; McGeehan, G. M. et al., Nature 1994, 370, 558-561), and thenafter, a similarity of the 3-dimensional structure of TACE (Maskos, K. et al., Proc. Natl. Acad. Sci. USA 1998, 95, 3408-3412) to that of MMP was also reported. Based on these, a number of patent applications of compounds having properties of inhibiting MMP and/or TACE have been filed (WO 97/18188, WO 97/20824, WO 97/22587, WO 98/16503, WO 98/16506, WO 98/16514, WO 98/16520, WO 98/24759, WO 98/32748, WO 98/37877, WO 98/38163, WO 98/38179, WO 98/43963, WO 98/50348, WO 98/51665, WO 99/37625, WO 99/38843, WO 99/41246, WO 99/42436, WO 99/52889, WO 99/52910, WO 99/58528, WO 99/58531, WO 99/61413, WO 99/65867, WO 00/09485, WO 00/12466, WO 00/12467, WO 00/12477, WO 00/12478, WO 00/50017, WO 00/51975, WO 00/59285, WO 00/69812, WO 00/71514, WO 00/75108, U.S. Pat. Nos. 5,985,900, 6,057,297, 6,162,821, JP-A-11-504015, EP 1 041 072 A). However, it has been reported that rats continuously administered with an agent which inhibits many kinds of MMPs at the same time had a hypertrophic degeneration on the cartilage growth plates (Nakajima, M., The Bone 2001, 15, 161-166) and that MT1-MMP (MMP14) knock out mouse was observed to present a symptom of arthritis (Holmbeck, K., et al., Cell 1999, 99, 81-92). Because of these reports and the fact that many MMPs are involved in the maintenance and homeostasis of extracellular matrices which form the basic structure of a living body, inhibiting the catalytic activities of many MMPs nonselectively is likely to cause serious adverse effects. Therefore, it is preferred that the compounds with the aim of suppressing the TNF-α production based on the TACE inhibition have very low inhibitory activities for other MMPs.
However, there are few patent applications concerned with compounds inhibiting TACE selectively (WO 98/38179, WO 00/00465, WO 00/09492, WO 00/23443, WO 00/35885, WO 00/44710, WO 00/44713, WO 00/44716, WO 00/44723, WO 00/44730, WO 00/44740, JP-A-11-343279, GB 2 326 881 A, WO 02/18326), and in most cases, there is poor selectivity in the compounds or no description on the results of their evaluation, and examples having obtained a high selectivity have scarcely ever been reported.
The present invention has been accomplished with the aim of treatment and prevention of TNF-α -mediated diseases, and objects of the present invention are to provide novel compounds and salts thereof which exhibit a TACE-selective inhibitory action and do not inhibit other MMPs, and to provide a pharmaceutical containing these as an effective component.